A few thoughts on cancer
and cancer family
syndromes
Pamela McGrann, MD.
Department of Medical Genetics
Family cancer syndromes
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There are about 1.4 million new
cancers diagnosed each year
~800,000 in men
~600,000 in women
Cancer family syndromes
Top 10 cancers
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Prostate
Breast
Lung and bronchus
Colorectal
lymphoma
Bladder
Melanoma
Uterus
Oropharynx
renal
Familial cancer syndromes
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~ 30-40 % of adult deaths
(nonaccidental, nonhomicidal) are due
to cancer
Cellular growth
Cells respond to:
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External growth factors
Steroid hormones
Cell-cell interactions
Cellular response to
growth factors
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Cellular differentiation
Cell growth
Cell division
Cell death (apoptosis)
Development of cancer
Cancer occurs when an accumulation of
gene mutations occur that affect:
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Regulation of cell growth and cell
division
Regulation of differentiation
The Knudson hypothesis
Dr. Knudson studied retinoblastoma and
noted:
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Some tumors unilateral, some bilateral
Some affected kids had a family hx of
retinoblastoma
The Knudson hypothesis
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The 2 hit theory of mutagenesis and
cancer
PNAS 68(4):820-823, April 1971
The Knudson hypothesis
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In the inherited form: one mutation is
inherited, and one is acquired.
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In the noninherited form both
mutations occur in somatic cells
Tumor suppressor genes
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The 1st tumor suppressor gene (RB1)
was cloned in 1986
Homozygously inactive in all
retinoblastoma tumors
Tumor suppressor genes
vs. oncogenes
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Tumor suppressor genes control cell growth
If one copy is inactivated, the other copy
can still accomplish the task.
Tumor suppressor genes act in a recessive
fashion
oncogenes originate from proto-oncogenes
Examples: growth factors, growth factor
receptors, signal transduction proteins,
nuclear transcription factors.
Familial cancers
characteristic features
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Several family members have the same or a
related cancer
Early age at onset of cancer (~10 yrs earlier
than average age at onset of the cancer in
the general population)
Presence of more than 1 type of cancer in a
single family member
Multifocal onset or onset in paired organs
Cancer family syndromes
Hereditary breast and ovarian cancer
 Autosomal dominant
 Accounts for 5-10% of breast and
ovarian cancers
 Genes – BRCA1 on chromosome
17q21
 BRCA2 on 13q12.3
Cancer family syndromes
BRCA1 and BRCA2
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Gene frequency: BRCA1: 1/5001/1000
BRCA2: unknown
BRCA1 cancer risks: breast cancer
87% by age 70 yrs.
44% ovarian cancer risk by age 70
20% risk prostate cancer
2-4% pancreatic cancer (nl <1%)
BRCA2
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breast cancer risk - 84% by age 70
Ovarian cancer risk - 27% by age 70
Male breast cancer risk - 6% by age
70
Familial adenomatous
polyposis
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Autosomal dominant
Incidence: 1/6000 – 1/13,000 (25-30%
are spontaneous new mutations)
Gene: APC
Location: 5q21q22
Diagnostic features: hundreds to
thousands of colonic polyps
Familial adenomatous
polyposis
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Polyps: as early as 7
years, as late as 70 yrs
Most FAP patients
have polyps by the late
teens
100% risk for colon ca
by midforties
Polyps may be in
duodenum and
stomach too
Lynch syndrome
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Autosomal dominant
Accounts for 5 – 10% of colon cancers
Genes: MLH1 at 3p21.3
MSH2 2p21
PMS1 2q32.2
PMS2 7p22
MSH6 2p16.3
Lynch syndrome:
function of the genes involved
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Not tumor suppressor genes or oncogenes
Lynch is due to DNA mismatch repair genes
MMR genes encode enzymes that survey
newly replicated DNA for errors and repair
mismatched bases in the DNA
Lynch syndrome:
the cancers
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Colon
Endometrial
Transitional cell cancers of the renal
collecting system
Pancreatic
Ovarian
Lynch syndrome:
penetrance
Lynch syndrome
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